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Pulmonology > Idiopathic Lung Disorders
Lymphangioleiomyomatosis
Article Last Updated: Aug 27, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Joel Moss, MD, PhD, Chief, Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health
Joel Moss is a member of the following medical societies: Alpha Omega Alpha, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians, and Phi Beta Kappa
Coauthor(s):
John A Kelly, MD, Assistant Professor of Medicine, Dartmouth Medical School; Consulting Staff Pulmonologist, Department of Microbiology and Immunology, White River Junction Veterans Affairs Medical Center
Editors: Ryland P Byrd, Jr, MD, Chief of Pulmonary Medicine, Medical Director of Respiratory Therapy, Quillen VA Medical Center; Professor, Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Professor of Medicine, University of California at Los Angeles School of Medicine; Director, Division of Pulmonary/Critical Care Medicine, Executive Vice Chair, Department of Medicine, Cedars-Sinai Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
LAM, progressive pulmonary dysfunction, abdominal tumors, angiomyolipomas, AML, abdominal mass, tuberous sclerosis, TSC, pulmonary disease, pneumothorax, lung disease, lung transplantation, lymphangioleiomyomatosis, LAM cell, lung cysts
Background
Lymphangioleiomyomatosis (LAM) is a rare disorder resulting from proliferation in the lung, kidney, and axial lymphatics of a neoplastic cell having a smooth muscle cell phenotype (LAM cell). Cystic destruction of the lung with progressive pulmonary dysfunction and the presence of abdominal tumors (eg, angiomyolipomas [AML], lymphangioleiomyomas) characterize the disease. Because this condition typically occurs in premenopausal women, involvement of the female hormones in disease pathogenesis is a current hypothesis.
Pathophysiology
LAM cell proliferation may obstruct bronchioles, possibly leading to airflow obstruction, air trapping, formation of bullae, and pneumothoraces. Obstruction of lymphatics may result in chylothorax and chylous ascites. Obstruction of venules may result in hemosiderosis and hemoptysis. Excessive proteolytic activity, which relates to an imbalance of the elastase/alpha1-antitrypsin system or metalloprotease (MMPs) and their inhibitors (tissue inhibitors of metalloproteases [TIMPS]) may be important in lung destruction and formation of cystlike lesions.
Frequency
United States
The frequency of LAM is unknown. To date, more than 500 cases exist in the United States. As the disease becomes better recognized because of increased awareness and better diagnostic techniques, the prevalence may increase.
International
The international frequency of LAM is unknown, though Europe and Japan report case series.
Mortality/Morbidity
Earlier reports indicate a grim prognosis with progressive respiratory failure and death within 10 years of diagnosis. Recent reports are more favorable, with 78% of patients who are affected alive at 8.5 years. The statistics may improve further as patients are diagnosed earlier (lead time bias) or with more benign disease.
Race
No racial predilection for LAM exists.
Sex
LAM primarily is a disease of women; however, rare case reports of LAM in men exist, primarily in men with tuberous sclerosis complex, an inherited disorder having shared features with LAM.
Age
Although primarily a disease of women of childbearing age, LAM has been reported in patients aged 12 years to patients older than 70 years. Some of the latter patients have been on hormone replacement therapy.
History
- Common symptoms
- Dyspnea
- Manifestations of pneumothorax
- Cough
- Less common symptoms
- Chest pain
- Chylothorax
- Chyluria
- Pericardial effusion
- Pneumoperitoneum
- Lymphedema
- Exacerbations of LAM are described during pregnancy, menstruation, and estrogen (ER) use.
Physical
- Examination usually normal
- Less common findings
- Crackles
- Wheezes
- Clubbing
- Pleural effusion
- Pneumothorax
- Ascites
- Signs of tuberous sclerosis
- Facial angiofibromas
- Ungual fibromas
- Hypomelanotic macules, ash-leaf spot
- Shagreen patch, a cluster of hamartoma typically located on the lower back
- Forehead plaque
- Retinal hamartoma
Causes
- The etiology of LAM is unknown; however, the fact that the condition occurs primarily in women who are premenopausal and is exacerbated by high ER states suggests a role for hormones in this condition.
- The link with tuberous sclerosis (TSC) suggests a genetic component (see Other Problems to be Considered).
Other Problems to be Considered
General conditions diagnosed in patients with LAM - Asthma
- Spontaneous pneumothorax
- Emphysema
Tuberous sclerosis - Probably a predisposing condition
- Several clinical features shared (lung, AML)
- Genetic features shared (TSC2 gene mutations in LAM lung tissue and AML)
Conditions with cysts, honeycombing, or interstitial pattern - Interstitial pulmonary fibrosis (unlike LAM, reduced lung volumes; however, patients with LAM who have had a pleurodesis may show decreased lung volumes)
- Eosinophilic granuloma (EG) (like LAM has increased lung volumes but may also have nodules; cysts in EG tend to have thicker walls than those in LAM)
- Bronchiolitis
Lymphatic disorders - Diffuse pulmonary lymphangiomatosis
- Lymphangiomas
- Pulmonary lymphangiectasis
Smooth-muscle proliferation - Leiomyosarcoma
- Smooth-muscle proliferation in the lung
- Benign metastasizing leiomyoma
Lab Studies
- Several case reports show an elevated cancer antigen 125 in patients with LAM and chylous ascites and/or pleural effusion.
Imaging Studies
- Chest radiograph findings
- May be normal
- Fine reticular or reticulonodular interstitial infiltrate - Lung volume not reduced
- Delicate honeycombing - More advanced disease
- Pleural effusions
- Pneumothoraces
- CT scan and high-resolution CT scan
- Diffuse thin-walled cysts - The defining characteristic appearance in LAM
- Intervening parenchyma usually normal
- Normal or increased lung volumes
- Adenopathy and thoracic duct dilatation
- Pleural effusion
- Pneumothorax
- Ground-glass opacities - Pulmonary hemorrhage
- Pericardial effusion
- Abdominal imaging by either ultrasound or CT scan
- AML
- Benign tumors (kidney, liver, spleen) containing smooth muscle, thick-walled blood vessels, and mature adipose tissue
- Retroperitoneal adenopathy
Other Tests
- Pulmonary function tests
- Decreased diffusing capacity for carbon monoxide - Most common abnormality seen, often markedly reduced. Hypoxemia at rest, worsening with exercise, is a common finding.
- Spirometry - Airflow obstruction most frequent abnormality; restriction (previous pleural disease) or mixed obstruction and restriction also seen
- Lung volumes - Increased total lung capacity (TLC) and increased residual volume to TLC ratio
Procedures
- In the past, open or thorascopic lung biopsies were required for histologic confirmation of the diagnosis.
- Histologic diagnosis now can be made by performing a transbronchial biopsy (TBB); the amount of tissue obtained from TBB may be insufficient to confirm a diagnosis. LAM cells react with human melanoma black (HMB)-45, an antibody generated against an extract of melanoma. HMB-45 staining is sensitive and specific for the presence of LAM cells and may help in confirming LAM on TBB. However, with classic high-resolution CT scans (particularly with extrathoracic features) and associated findings of LAM (eg, tuberous sclerosis complex, AML, lymphangioleiomyomas), histologic confirmation may be unnecessary.
Histologic Findings
Macroscopic pathology
- Lung - Cysts evenly distributed in all lung fields
- Lymph nodes (retroperitoneal and pelvic) - Pale and spongy; large chyle-filled cysts within the axial lymphatic system
- Thoracic duct - Large, spongy, and sausagelike
Microscopic pathology
- Lung
- Proliferation of neoplastic LAM cells (spindle-shaped cells with small nuclei, larger epithelioid cells with clear cytoplasm and round nuclei) having a smooth muscle cell phenotype
- Loss of alveoli with cyst formation
- Cystic spaces with LAM cells in their walls
- Smooth-muscle proliferation in bronchiolar walls, causing airway narrowing, thickened arterial walls with venous occlusion, and hemosiderosis
- Involved lymph nodes and thoracic duct - Interlacing bundles of LAM cells, which may invade the wall of the lymphatics
- Immunohistochemical staining
- Reactivity with anti—alpha-smooth actin antibodies supports smooth-muscle differentiation.
- ER and progesterone receptors are present, but their role is unclear.
- Monoclonal antibody HMB-45, generated against melanoma extract and recognizing cells with epithelioid features (rarely, spindle cells are HMB-45 positive), may help confirm the diagnosis of LAM on biopsy.
- Immunohistochemical staining may define renal and hepatic AML.
Medical Care
- General care
- Pleural effusions - Chemical pleurodesis; surgical obliteration of the pleural space; medium-chain triglyceride (MCT [not a component of chyle]), lipid-free diet to reduce chyle flow (utility unknown)
- Ascites - Paracentesis, MCT diet (utility unknown)
- Pulmonary dysfunction - General pulmonary care (eg, vaccines), bronchodilators (+/- benefit), supplemental oxygen, pulmonary rehabilitation
- Lung transplantation
- Hormonal manipulation
- Medroxyprogesterone - Utility not known, recent case series does not support use
- Gonadotropin-releasing hormone agonists - Utility not known, few case reports support use
- Tamoxifen not recommended
- Oophorectomy not thought to be effective based on recent case series
- New experimental therapies
- Rapamycin-initial trials in AML, now being investigated as a therapy in pulmonary LAM
- Doxycycline-anti-angiogenic, antibiotic and matrix effects
- Octreotide
Surgical Care
- Management of recurrent pneumothoraces or pleural effusions may require surgical intervention; in addition, patients with AML can develop complications (eg, hemorrhage), requiring intervention.
- Consider lung transplantation for patients with end-stage pulmonary disease.
Consultations
- Pulmonologist
- Pulmonologist helps establish the diagnosis and monitor pulmonary function.
- A pulmonologist can address issues such as vaccinations, oxygen therapy, and pulmonary rehabilitation.
- Depending on disease severity, referral to a transplant center may be beneficial. Consider patient referral to a center with an interest in LAM.
- Endocrinologist and/or obstetrician-gynecologist
- These specialists may help to address the hormonal issues involved, particularly when considering hormonal manipulation.
- An endocrinologist can assist with prophylaxis and treatment of osteoporosis in patients in whom exogenous ER is contraindicated.
- A urologist may assist with renal AML management.
- A dietitian may help to consult patients on MCT diets for chylous ascites or pleural effusions.
- Consider referral to specialist center.
Diet
- Most patients with LAM do not have special dietary requirements; however, if a patient is on therapies to lower ER or is postmenopausal and not on ER replacement therapy, address other cardiac risk factors (eg, cholesterol levels).
- Some patients with chylous effusions or ascites may try an MCT diet (see Medical Care).
Activity
- Although the literature is sparse with regard to activities that can cause barotrauma in patients with LAM, theoretical concern exists regarding certain activities such as flying, particularly in patients with LAM and a history of prior pneumothorax.
- Reports show pregnancy exacerbating the disease; therefore, specialists generally recommend that patients with LAM avoid becoming pregnant. However, some patients with mild disease have had a normal pregnancy with little deterioration in lung function.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Rapamycin: The TSC genes are believed to regulate a protein, called mammalian target of rapamycin (mTOR), which is known to control cell growth and proliferation. Rapamycin inhibits the activity of mTOR. In a phase I/II clinical trial, use of rapamycin was associated with a reduction in size of renal AMLs. A second clinical trial is underway looking at the effect of rapamycin on pulmonary function.
Doxycycline: Doxycycline, a drug with antibiotic, anti-angiogenic, and anti-MMP activities is being tested for its ability to improve pulmonary function in LAM.
Drug Category: Progestins
Because LAM is predominantly a disease of premenopausal women, researchers hypothesize that hormones, especially ERs, play a pathogenic role. A recent retrospective review of LAM does not support the use of progestins in the disease.
| Drug Name | Medroxyprogesterone acetate (Provera, Depo-Provera) |
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| Description | A derivative of progesterone. Reports describe stabilization or occasional improvement with progesterone therapy, especially in the presence of chylous effusions or ascites; however, data supporting its use in LAM are not strong. |
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| Adult Dose | 400-1600 mg IM qmo
20-60 mg PO qd |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; cerebral apoplexy; pregnancy; breast malignancy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction |
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| Interactions | Aminoglutethimide can depress serum levels of medroxyprogesterone acetate; the following laboratory tests can be affected: plasma and urine steroid levels, certain coagulation levels, protein-bound iodine, and certain thyroid function tests |
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| Pregnancy | X - Contraindicated; benefit does not outweigh risk
|
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| Precautions | Perform a pretreatment breast and pelvic examinations; weight gain and/or fluid retention can occur; caution in patients with history of depression or seizures; observe patients diagnosed with diabetes for deterioration in glucose tolerance; perform liver function tests and bone density determinations; caution in asthma, renal or cardiac dysfunction, or thromboembolic disorders
Avoid in patients with meningioma |
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Complications
- Pneumothorax
- Hemoptysis
- Chylothorax
- Ascites
- Chyloptysis
- Chyluria
- Pericardial effusion
- Pneumoperitoneum
- Acute abdomen
- Lymphedema
- Respiratory failure
Prognosis
- As many as 78% of patients are alive at 8.5 years after the disease onset.
- Poor prognostic factors
- Reduced forced expiratory volume in 1 second and/or diffusing capacity for carbon monoxide
- Increased TLC
- Histologically, a poor LAM histology score, which quantifies the involvement of the lung with both LAM cells and cysts
Patient Education
- Inform patients about their disease because education is an important issue in this condition. An excellent resource is the LAM Foundation .
Medical/Legal Pitfalls
- Failure to diagnose LAM
- Failure to consider LAM in women of childbearing years who present with recurrent pneumothoraces, unexplained dyspnea, or chylous effusion
- Failure to look for LAM in patients with TSC or AML of the kidneys
This work was supported in part by the Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute.
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Lymphangioleiomyomatosis excerpt Article Last Updated: Aug 27, 2007
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